Indole derivatives

ABSTRACT

Compounds are disclosed of formula (I) ##STR1## wherein R 1  represents H or C 1-6  alkyl; 
     R 2  represents H, C 1-6  alkyl, C 3-7  cycloalkyl, C 3-6  alkenyl, phenyl or phen(C 1-3 )alkyl in which the phenyl ring is optionally substituted by halogen, C 1-4  alkoxy, hydroxy or C 1-3  alkyl; 
     R 3  represents H, C 1-3  alkyl, --CO 2  R 5 , --COR 5 , --COCO 2  R 5  or --CONHR 5  where 
     R 5  represents H, C 1-4  alkyl, C 3-7  cycloalkyl, C 2-4  alkenyl, aryl or ar(C 1-4 )alkyl in which the aryl group is optionally substituted by halogen, C 1-4  alkoxy, C 1-4  alkyl or hydroxy) (provided that where R 3  represents --CO 2  R 5 , R 5  is other than H); 
     R 4  represents H, C 1-3  alkyl, C 3-6  alkenyl, phenyl or phen (C 1-3 )alkyl; 
     A-B represents CH--CH 2  --or C═CH-- 
     D represents --CO-- or --SO 2  -- 
     n represents 0, 1-5; 
     provided that when D represents --SO 2 , n is 2, R 3  represents H and R 4  represents H or C 1-3  alkyl, R 2  is other than H or C 1-6  alkyl; and pharmaceutically acceptable salts and solvates (for example hydrates) thereof. 
     The compounds are indicated as useful for the treatment of migraine, cluster headache, chronic paroxysmal hemicrania and headache associated with vascular disorders. 
     Processes and intermediates for their preparation and pharmaceutical compositions containing them are also disclosed.

This application is a continuation of application Ser. No. 07/231,260,filed Aug. 12, 1988, now abandoned.

This invention relates to indole derivatives, to processes for theirpreparation, to pharmaceutical compositions containing them and to theirmedical use, in particular to compounds and compositions of use in thetreatment of migraine.

It has been suggested that the pain of migraine may be associated withexcessive dilatation of the cranial vasculature and known treatments formigraine include the administration of compounds having vasoconstrictorproperties such as ergotamine. However, ergotamine is a non-selectivevasoconstrictor which constricts blood vessels throughout the body andhas undesirable and potentially dangerous side effects. Migraine mayalso be treated by administering an analgesic usually in combinationwith an entimetic but such treatments are of limited value.

More recently, indole derivatives which are selective 5HT₁ -likereceptor agonists and which exhibit selective vasoconstrictor activityhave been described in the art as useful in the treatment of migraine(see for example A-Doenicke, J-Brand, V. L. Perrin, Lancet, 1988,1309-1311).

We have not found a novel group of indole derivatives which exhibit 5HT₁-like receptor agonist activity and selective vasoconstrictor activity.

Thus, the present invention provides an indole of formula (I): ##STR2##wherein R₁ represents a hydrogen atom or a C₁₋₆ alkyl group;

R₂ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇ cycloalkylgroup, a C₃₋₆ alkenyl group, or a phenyl or phen(C₁₋₃)alkyl group inwhich the phenyl ring is optionally substituted by a halogen atom, aC₁₋₄ alkoxy group, a hydroxy group or a C₁₋₃ alkyl group;

R₃ represents a hydrogen atom, a C₁₋₃ alkyl group or a group --CO₂ R₅,--COR₅, --COCO₂ R₅ or --CONHR₅ where R₅ represents a hydrogen atom, aC₁₋₄ alkyl group, a C₃₋₇ cycloalkyl group, a C₂₋₄ alkenyl group or anaryl or ar(C₁₋₄)alkyl group in which the aryl group may be unsubstitutedor substituted by a halogen atom, a C₁₋₄ alkoxy group, a C₁₋₄ alkylgroup or a hydroxy group (provided that when R₃ represents --CO₂ R₅, R₅is other than hydrogen);

R₄ represents a hydrogen atom, a C₁₋₃ alkyl group, a C₃₋₆ alkenyl group,a phenyl group or a phen(C₁₋₃)alkyl group;

A--B represents the group CH--CH₂ -- or C═CH--;

D represents the group --CO-- or --SO₂ --;

n represents zero or an integer from 1 to 5;

and pharmaceutically acceptable salts or solvates (for example hydrates)thereof provided that when D represents the group --SO₂ --, n is 2, R₃is hydrogen and R₄ is hydrogen or C₁₋₃ alkyl, then R₂ is other thanhydrogen or C₁₋₆ alkyl.

Referring to the general formula (I), an alkyl group either as such oras part of an alkoxy or phenalkyl group may be a straight chain orbranched chain alkyl group such as a methyl, ethyl or prop-2-yl group.

A C₃₋₇ cycloalkyl group may be a cyclopropyl, cyclobutyl, cyclopentyl,cyclohexykl or cycloheptyl group.

A C₃₋₆ alkenyl group may be, for example, a propenyl, 2-propenyl orbutenyl group. Where R₂ and/or R₄ represents an alkenyl group, it willbe appreciated that the double bond may not be adjacent to the nitrogenatom.

When R₂ represents a substituted or unsubstituted phen(C₁₋₃)alkyl group,the alkyl moiety of the group is preferably a methyl or ethyl moiety.

A halogen substituted in the compounds of general formula (I) may be afluorine, chlorine, bromine or iodine atom. A C₁₋₄ alkoxy group may be,for example, a methoxy or ethoxy group.

An aryl group, either as such or as part of an ar(C₁₋₄)alkyl group ispreferably phenyl.

In one preferred class of compounds represented by formula (I), Drepresents the group --SO₂ --.

In another preferred class of compounds of formula (I), D represents thegroup --CO--.

Another preferred class of compounds of formula (I) is that in whichA--B represents the group --CH--CH₂ --.

In the compounds of formula (I), R₁ preferably represents a hydrogenatom or a C₁₋₃ alkyl group such as methyl.

R₂ in the compounds of formula (I) preferably represents a hydrogen atomor a C₁₋₃ alkyl group such as methyl. In an alternative preference, R₂represents a phen(C₁₋₃)alkyl group such as phenethyl.

Conveniently R₁ and R₂ when considered together comprise from 1 to 3carbon atoms. Obviously when R₁ and R₂ comprise an alkyl groupcontaining one carbon atom, then one of R₁ or R₂ is hydrogen.

In the compounds of formula (I), R₃ may be, for example, a methyl groupbut is preferably a hydrogen atom.

The substituent R₄ is preferably a C₁₋₃ alkyl group such as methyl.

n preferably represents 0, 1 or 2.

An alternative preferred class of compounds within the scope of formula(I) has the formula (Ia) ##STR3## wherein R_(1a) represents a hydrogenatom or a C₁₋₆ (preferably C₁₋₃) alkyl group;

R_(2a) represents a hydrogen atom or a C₁₋₆ (preferably C₁₋₃)alkylgroup;

R_(3a) represents a hydrogen atom or a C₁₋₃ alkyl group;

R_(4a) represents a hydrogen atom or a C₁₋₃ alkyl group;

and pharmaceutically acceptable salts and solvates (for examplehydrates) thereof.

Suitable pharmaceutically acceptable salts are those conventionallyknown in the art. Examples of physiologically acceptable salts includeacid addition salts formed with inorganic acids, such as hydrochlorides,hydrobromides, phosphates and sulphates, and with organic acids, forexample tartrates, maleates, fumarates, succinates and sulphonates.Other salts which are not pharmaceutically acceptable may be useful inthe preparation of compounds of formula (I) and these form a furtherpart of the invention.

The invention embraces all optical isomers of the compounds of formula(I) and their mixtures, including racemic mixtures thereof. Theinvention also includes within its scope all geometric isomers of thecompounds of formula (I).

The selective 5HT₁ -like receptor agonist activity and selectivevasoconstrictor activity of the compounds of the invention have beendemonstrated in vitro. In addition, certain of the compounds of theinvention have been found to selectively constrict the carotid arterialbed of the anaesthetised dog whilst having negligible effect on bloodpressure.

Compounds of the invention are useful in treating conditions associatedwith cephalic pain. In particular, the compounds are useful in thetreatment of migraine, cluster headache, chronic paroxysmal hemicraniaand headache associated with vascular disorders and in alleviating thesymptoms associated therewith.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt or solvate (e.g. hydrate) thereof andformulated for administration by any convenient route. Such compositionsare preferably in a form adapted for use in medicine, in particularhuman medicine, and can conveniently be formulated in conventionalmanner using one or more pharmaceutically acceptable carriers orexcipients.

In a further aspect there is provided a compound of formula (I) or asalt or solvate thereof for use in therapy, in particular in humanmedicine. It will be appreciated that use in therapy embraces but is notnecessarily limited to use of a compound of formula (I) or a salt orsolvate thereof as an active therapeutic substance.

There is also provided as a further aspect of the invention the use of acompound of formula (I) in the preparation of a medicament for use inthe treatment of conditions associated with cephalic pain, in particularmigraine, cluster headache, chronic paroxysmal hemicrania and headacheassociated with vascular disorders.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, comprising administration of aneffective amount of a compound of formula (I) or salt or solvate thereofin particular in the treatment of conditions associated with cephalicpain.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.Compounds according to the invention may be administered as the rawchemical but the active ingredient is preferably presented as apharmaceutical formulation.

The active ingredient may conveniently be presented in unit dose form. Aconvenient unit dose formulation contains the active ingredient compoundin an amount of from 0.1 mg to 100 mg.

The compounds according to the invention may for example be formulatedfor oral, sub-lingual buccal, parenteral, rectal or intranasaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium phosphate); lubricants (e.g. magnesium stearate, talc orsilica); disintegrants (e.g. potato starch or sodium starch glycollate);or wetting agents (e.g. sodium lauryl sulphate). The tablets may becoated by methods well known in the art. Liquid preparations for oraladministration may take the form of, for example, solutions, syrups orsuspensions, or they may be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations may be prepared by conventional means with pharmaceuticallyacceptable additives such as suspending agents (e.g. sorbitol syrup,methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g.lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily estersor ethyl alcohol); and preservatives (e.g. methyl orpropyl-p-hydroxybenzoates or sorbic acid).

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by injection, conveniently intravenous, intramuscular orsubcutaneous injection, for example by bolus injection or continuousintravenous infusion. Formulations for injection may be presented inunit dosage form e.g. in ampoules or in multi-dose containers, with anadded preservative.

The compositions may take such forms as suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glyceride.

Tablets for sub-lnigual administration may be formulated in a similarmanner.

For intranasal administration the compounds of the invention may beused, for example, as a liquid spray, as a powder or in the form ofdrops.

For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs or a nebuliser, with the use of asuitable propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of a compound ofthe invention and a suitable powder base such as lactose or starch.

It will be appreciated that the precise administered will depend on theage and condition of the patient, the particular compound used and thefrequency and route of administration. The compound may be administeredin single or divided doses and may be administered one or more times,for example 1 to 4 times per day.

A proposed dose of the compounds of the invention for oral, sub-lingualparenteral, buccal, rectal or intranasal administration to man (ofapproximately 70 kg bodyweight) for the treatment of migraine is 0.1 to100 mg of the active ingredient per unit does which could beadministered, for example, 1 to 4 l times per day.

For oral administration a unit does will preferably contain from 2 to 50mg of the active ingredient. A unit dose for parenteral administrationwill preferably contain 0.2 to 5 mg of the active ingredient.

Aerosol formulations are preferably arranged so that each metered doseor `puff` delivered from a pressurised aerosol contains 0.2 mg to 2 mgof a compound of the invention, and capsules and cartridges deliveredfrom an insufflator or an inhaler, contain 0.2 mg to 20 mg of a compoundof the invention. The overall daily dose by inhalation with an aerosolwill be within the range 1 mg to 100 mg. Administration may be severaltimes daily, for example from 2 to 8 times, giving for example 1, 2 or 3doses each time.

Dosages of the compounds of the invention for rectal, sub-lingual orintranasal administration are similar to those for oral administration.

The compounds of the invention may, if desired, be administered incombination with one or more other therapeutic agents, such asanalgesics, anti-inflammatory agents and anti-nauseants, and formulatedfor administration by any convenient route in conventional manner.Appropriate doses will be readily appreciated by those skilled in theart.

According to another aspect of the invention, compounds of generalformula (I) and physiologically acceptable salts and solvents (e.g.hydrates) thereof, may be prepared by the general methods outlinedbelow. In the following processes, R₁, R₂, R₃ and R₄, the group A--B,the group D, and n are as defined for the general formula (I) unlessotherwise specified.

According to one general process (A), compounds of formula (I) whereinA--B is the group C═CH may be prepared by condensing a compound offormula (II): ##STR4## or a protected or activated derivative thereof,with a piperidone of formula (III): ##STR5## or a salt or protectedderivative thereof.

The condensation reaction may be effected in a suitable reaction mediumin the presence of an acid or a base, conveniently at a temperature of25° to 120° C.

Acids which may be employed in the above process include organic andinorganic acids such as sulphonic acids (e.g. p-toluenesulphonic acid),carboxylic acids (e.g. acetic acid) and preferably strong inorganicacids such as polyphosphoric acid, sulphuric acid and hydrochloric acid.Suitable solvents for the reaction include inert solvents such as ethers(e.g. tetrahydrofuran or dioxan), alcohols (e.g. ethanol) andchlorinated hydrocarbons (e.g. chloroform or carbon tetrachloride). Insome cases the acid may also act as the reaction solvent.

It will be appreciated that in order for the above process to beeffected in the presence of a base, R³ should represent a hydrogen atom.

Bases which may be employed in the above process include alkali metalhydroxides (e.g. potassium hydroxide), alkali metal alkoxides (e.g.sodium or potassium methoxide, ethoxide or t-butoxide), alkali metalhydrides (e.g. sodium hydride) and alkali metal amides (e.g. sodamide).Suitable solvents for the reaction include alcohols (e.g. methanol orethanol) ethers (e.g. tetrahydrofuran or dioxan) and dimethylsulphoxide.

Intermediates of formula (II) may be prepared by conventional methodsfor example by reacting an amine of formula R₁ R₂ NH with the3-unsubstituted analogues of compounds of formula (IV) (as describedhereinafter) using the methods described for process (B) hereinafter.

According to another general process (B), a compound of formula (I) mayalso be prepared by condensing an amine of formula R₁ R₂ NH with an acidof general formula (IV). ##STR6## or an acylating agent correspondingthereto, or a salt (for example, an organic or inorganic acid additionsalt such as the hydrochloride, hydrobromide, maleate, sulphate orcreatinine sulphate adduct) or a protected derivative thereof.

Acylating agents corresponding to the acid of general formula (IV) whichmay conveniently be used in the above process include acid halides (forexample carboxylic acid chlorides and sulphonyl chlorides), alkyl esters(for example the methyl or ethyl esters), activated esters (for example,the 2-(1-methylpyridinyl)ester), mixed anhydrides (for example,diphenylcarbamic anhydride or pivalic anhydride), or other activatedcarboxylic acid derivatives such as those conveniently used in peptidesynthesis.

The condensation process involving the acylating agents may be effectedin a suitable reaction medium which may be aqueous or non-aqueous andconveniently at a temperature of from -70° to +150° C. Thus thecondensation reaction using an acid halide, anhydride or activated estermay be effected in a suitable reaction medium such as an amide (e.g.,N,N'-dimethylformamide), an ether (e.g. tetrahydrofuran), a nitrile(e.g. acetonitrile), a haloalkane (e.g. dichloromethane) or mixturesthereof, optionally in the presence of a base such as pyridine ortriethylamine or an inorganic base as calcium carbonate or sodiumbicarbonate. The condensation reaction using an alkyl ester may beeffected in a suitable reaction medium such as an alcohol (e.g.methanol), an amide (e.g. dimethylformamide), an ether (e.g.tetrahydrofuran) or mixtures thereof and conveniently at a temperatureof from 0° to 100° C. In some instances, the amine R₁ R₂ NH may itselfact as reaction solvent.

The reaction involving condensation of an amine R₁ R₂ NH with acarboxylic acid of general formula (IV) is desirably conducted in thepresence of a coupling agent such as carbonyl dimidazole orN,N'-dicyclohexylcarbodiimide. The condensation reaction may be carriedout in a suitable reaction medium such as an ether (for example,tetrahydrofuran), a haloalkane (for example, dicloromethane), a nitrile(for example, acetonitrile) or an amide (for example, dimethylformamide)conveniently at a temperature of from -5° to +30° C. The reaction mayalso be carried out in the absence of a coupling agent in a suitablereaction medium such as a hydrocarbon (for example, toluene or xylene)conveniently at a temperature of from 50° to 120° C.

Where it is desired to prepare a compound of formula (I) in which R₁ andR₂ are both hydrogen atoms, ammonia may be used in the form of aqueousammonia or in a solvent such as methanol.

Compounds of formula (IV) and acylating agents corresponding thereto,such as the alkyl esters, are novel and as such constitute a furtherfeature of the invention. Compounds of formula (IV) or acylating agentscorresponding thereto may be prepared by methods analogous to thosedescribed in UK Patent Specification 2035210 and `A Chemistry ofHeterocyclic compounds--Indles Part II`, Chapter VI, edited by W. J.Houlihan (1972) Wiley Interscience, New York or by processes, such asprocess (A), as described herein.

According to another general process (C), compounds of formula (I) maybe prepared by cyclisation of a compound of formula (V) ##STR7##

The process is desirably carried out in the presence of polyphosphateester in a reaction medium which may comprise one or more organicsolvents, preferably halogenated hydrocarbons such as chloroform,dichlormethane, dichloroethane, dichlorodifluoromethane, or mixturesthereof. Polyphosphate ester is a mixture of esters which may beprepared from phosphorus pentoxide, diethylether and chloroformaccording to the method described in `Reagents for Organic Synthesis`,(Fieser and Fieser, John Wiley and Sons 1967).

Alternatively the cyclisation may be carried out in aqueous ornon-aqueous media, in the presence of an acid catalyst. When an aqueousmedium is employed this may be an aqueous organic solvent such as anaqueous alcohol (e.g. methanol, ethanol or isopropanol) or an aqueousether (e.g. dioxan or tetrahydrofuran) as well as mixtures of suchsolvents and the acid catalyst may be for example an inorganic acid suchas concentrated hydrochlorid, polyphosphoric or sulphuric acid. (In somecases the acid catalyst may also act as the reaction solvent). In ananhydrous reaction medium, which may comprise one or more alcohols orethers (e.g. as described above) or esters (e.g. ethyl acetate), theacid catalyst will generally be a Lewis acid such as boron trifluorideor zinc or magnesium chloride. The cyclisation reaction may convenientlybe carried out at temperatures of from 20° to 200° C. preferably 50° to125° C.

According to a particular embodiment of this process, compounds ofgeneral formula (I) may be prepared directly by the reaction of acompound of general formula (VI): ##STR8## or a salt thereof, with acompound of formula (VII): ##STR9## or a salt or protected derivativethereof (such as an acetal e.g. formed with an appropriatealkylorthoformate), using the appropriate conditions as described above.It will be appreciated that in this embodiment a compound of formula (V)is formed as an intermediate and may be reacted in situ to form thedesired compound of formula (I).

Compounds of the general formula (V) may be isolated as intermediatesduring the process for the preparation of compounds of general formula(I) wherein a compound of formula (VI), or a salt thereof, is reactedwith a compound of formula (VII) or a salt or protected derivativethereof, in a suitable solvent such as an aqueous alcohol (e.g.methanol) and at a temperature of, for example, from 20° to 100° C. Ifan acetal of a compound of formula (VII) is used it may be necessary tocarry out the reaction in the presence of an acid (for example, aceticor hydrochloric acid). In some cases the acid may also act as thereaction solvent.

Compounds of general formula (VI) may be prepared in a number ofconventional steps from compounds of formula (VIII) ##STR10##

For example, a compound of formula (VIII) may be reduced by catalyticdehydrogenation using a catalyst such as palladium on charcoal to givean amine which may be diazotised using, for example nitrous acid. Theproduct of this reaction may then be reduced using, for example,stannous chloride, to give a compound of formula (VI).

According to another general process (D), a compound of formula (I)wherein n represents 2 to 5 may be prepared by reduction of a compoundof formula (IX) ##STR11## (wherein --Q═CH represents a C₂₋₅ alkenylchain).

The reduction may be effected using similar reaction conditions to thosedescribed for general process (A) above.

Compounds of formula (IX) are themselves novel and form a furtherfeature of the invention.

Compounds of formula (IX) may be prepared by condensing a compound offormula (X) ##STR12## (wherein X represents a leaving atom or group suchas a halogen atom for example a bromine atom) with an alkene R₁ R₂NDQ═CH₂.

The reaction will generally be effected in the presence of a palladiumcatalyst and a base. The catalyst may be, for example, palladium oncharcoal or a palladium salt. Palladium salts which may be employed ascatalysts include salts of organic acids such as acetates or salts ofinorganic acids such as chlorides or bromides. The base may be, forexample, a tertiary nitrogen base such as triethylamine ortri-n-butylamine or an alkali metal carbonate such as sodium carbonate.The reaction may optionally be carried out in the presence of aphosphine, for example a triarylphosphine such as triphenylphosphine ortri-o-tolylphosphine. A phosphine should be present when the process iseffected with a compound of formula (XI) wherein X represents a bromineatom.

General process (D) may be effected in the presence or absence ofsolvent. An anhydrous or aqueous reaction medium comprising one or moresolvents may be employed. Suitable solvents include nitriles, forexample, acetonitrile, alcohols, for example methanol, amides, forexample dimethylformamide, N-methylpyrrolidine orhexamethylphosphoramide; and water. The reaction may conveniently becarried out at a temperature of from 25° to 200° C., preferably 75° to150° C.

Compounds of formula (X) may be prepared from known compounds by methodsanalgous to those described herein.

According to another general process (E) a compound of formula (I)according to the invention may be converted into another compound of theinvention using conventional procedures.

For example, compounds of formula (I) wherein A--B is the group--CH--CH₂ -- may be prepared by reduction of the corresponding compoundsof formula (I) wherein A--B is the group --CH═CH--. The reductionprocess may conveniently be carried out in the presence of hydrogen anda noble metal catalyst, such as palladium, Raney nickel, platinum,platinum oxide or rhodium which may be supported, for example, oncharcoal. Alternatively a homogenous catalyst such astris(triphenylphosphine) rhodium chloride may be used. The reduction maybe carried out in a solvent such as an alcohol e.g. methanol or ethanol,an ether e.g. dioxan, an ester e.g. ethyl acetate or an amide e.g.dimethylformamide and conveniently at a temperature of from -10° to +50°C.

It should be noted however, that the conditions for the reduction of thegroup A--B when it represents --C═CH--, to the group --CH--CH₂, may alsoeffect cleavage of any benzyl groups present or reduction of any otheralkenyl group present to an alkyl group.

According to one embodiment of this process, a compound of generalformula (I) where A--B represents --CHCH₂ -- and R₄ is a hydrogen atom,may be prepared by reduction of a corresponding compound of generalformula (I) wherein R₄ is a benzyl group, for example with hydrogen inthe presence of a catalyst e.g. 10% palladium on charcoal.

According to a further embodiment, a compound of general formula (I)where A--B represents --CHCH₂ -- and R₂ represents a C₃₋₆ alkyl groupmay be prepared by reduction of the corresponding compound of formula(I) wherein A--B represents C═CH or --CHCH₂ -- and R₂ represents a C₃₋₆alkenyl group. The reduction process may be effected using theconditions as described above for the reduction of the group A--B.

According to another embodiment of general process (E), a compound offormula (I) wherein one or more of R₁, R₂, R₃ and R₄ represent hydrogenatoms may be alkylated using conventional techniques. It will beunderstood that the term `alkylation` embraces the introduction of analkyl, cycloalkyl alkenyl or phenylalkyl group. The reaction may beeffected using a suitable alkylating agent such as an alkyl halide,alkyl tosylate or dialkylsulphate. The alkylation reaction mayconveniently be carried out in an inert organic solvent such as an amide(e.g. dimethylformamide) or an ether (e.g. tetrahydrofuran) preferablyin the presence of a base. Suitable bases include, for example, alkalimetal hydrides, such as sodium hydride, alkali metal carbonates, such assodium carbonate or alkali metal alkoxides such as sodium or potassiummethoxide, ethoxide or t-butoxide. The alkylation reaction isconveniently carried out at a temperature of from 25° to 100° C.

According to a still further embodiment, a compound of general formula(I) in which R₃ represents a group --CO₂ R₅, --COR₅, --COCOR₅ or --CONHR₅ may be prepared by acylating the corresponding compound of formula(I) wherein R₃ represents a hydrogen atom, or a protected derivativethereof. Acylating agents corresponding to the group R³ which may beused in this general process include acid halides (e.g. acid chloridessuch as acetyl chloride); alkyl haloformates (e.g. methyl or ethylchloro- formate); mixed or symmetrical anhydrides (e.g. acetic anhydrideor benzoic anhydride); carbonates (e.g. diethyl carbonate); andisocyanates (e.g. methyl isocyanate).

The reaction is conveniently effected in the presence of a base, such asan alkali metal hydride, e.g. sodium or potassium hydride; an alkalimetal carbonate e.g. sodium or potassium carbonate; an alkali metalalkoxide e.g. potassium t-butoxide; butyllitium; or an organic tertiaryamine, e.g. triethylamine, or pyridine. Suitable solvents which may beemployed in the acylation process include amides e.g. dimethylformamide,or dimethylacetamide; ethers, e.g. tetrahydrofuran or dioxan;halogenated hydrocarbons e.g. methylene chloride; nitriles e.g.acetonitrile and esters e.g. ethyl acetate. The reaction mayconveniently be effected at a temperature in the range -10° to +150° C.

Alternatively the acylation may be effected in a two-phase reactionmedium, in the presence of a phase transfer catalyst, such astetrabutylammonium hydrogen sulphate or tetraethylammonium bromide. Thusfor example the acylating agent may be reacted with a compound offormula (I) in an inert organic solvent, (e.g. a halogenated hydrocarbonsuch as methylene chloride), and an aqueous solution of a base (e.g. 50%sodium hydroxide) containing a phase transfer catalyst.

It will be appreciated that in compounds of general formula (I) whereinR₄ represents hydrogen, it will be necessary to protect the group NR₄during the acylation process. Suitable protecting groups which may beused include conventional amino protecting groups as described forgeneral process (F) hereinafter.

According to another general process (F), a compound of general formula(I) according to the invention, or a salt thereof may be prepared bysubjecting a protected derivative of general formula (I) or a saltthereof to reaction to remove the protecting group or groups.

Thus, at an earlier stage in the preparation of a compound of generalformula (I) or a salt thereof it may have been necessary and/ordesirable to protect one or more sensitive groups in the molecule toprevent undesirable side reactions.

The protecting groups used in the preparation of compounds of formula(I) may be used in conventional manner. See for example `ProtectiveGroups in Organic Chemistry` Ed.J.F.w. McOmie (Plenum Press 1973) or`Protective Groups in Organic Synthesis` by Theodora W Greene (JohnWiley and Sons 1981).

In compounds of general formula (I) wherein R₄ represents hydrogen thegroup NR₄ may be protected for example by protonation or with aconventional amino protecting group. Such groups may include for examplearakyl groups, such as benzyl, diphenylmethyl or triphenylmethyl groups;and acyl groups such as N-benzyloxycarbonyl or t-butoxycarbonyl orphthaloyl. The indole nitrogen may also be protected, for example by anaralkyl group such as benzyl. Thus, compounds of general formula (I)wherein one or more of the groups R₃ and R₄ represents hdyrogen may beprepared by deprotection of a corresponding protected compound.

Removal of any amino protecting groups present may be achieved byconventional procedures. Thus an aralkyl group such as benzyl, may becleaved by hydrogenolysis in the presence of a catalyst (e.g. palladiumon charcoal); an acyl group such as N-benzyloxycarbonyl may be removedby hydrolysis with, for example, hydrogen bromide in acetic acid or byreduction, for example by catalytic hydrogenation. The phthaloyl groupmay be removed by hydrazinolysis (for example, by treatment withhydrazine hydrate) or by treatment with a primary amine such asmethylamine.

As will be appreciated, in some of the general processes (A) to (E)described above it may be necessary or desired to protect any sensitivegroups in the molecule as just described. Thus, a reaction stepinvolving deprotection of a protected derivative of general formula (I)or a salt thereof may be carried out subsequent to any of the abovedescribed processes (A) to (E).

Thus, according to a further aspect of the invention, the followingreactions may, if necessary and/or desired by carried out in anyappropriate sequence subsequent to any of the processes (A) to (E).

(i) removal of any protecting groups; and

(ii) conversion of a compound of general formula (I) or a salt thereofinto a physiologically acceptable salt or solvate (for example, hydrate)thereof.

Where it is desired to isolate a compound of the invention as a salt,for example as an acid addition salt, this may be achieved by treatingthe free base of general formula (I) with an appropriate acid,preferably with an equivalent amount, or with creatinine sulphate in asuitable solvent (e.g. aqueous ethanol).

As well as being employed as the last main step in the preparativesequence, the general methods indicated above for the preparation of thecompounds of the invention may also be used for the introduction of thedesired groups at an intermediate stage in the preparation of therequired compound. It should therefore be appreciated that in suchmulti-stage processes, the sequence of reactions should be chosen inorder that the reaction conditions do not affect groups present in themolecule which are desired in the final product.

The invention is further illustrated by the following non-limitingExamples. All temperatures are in 0° C. Solutions were dried with Na₂SO₄ unless otherwise indicated. Chromatography was carried out by flashchromatography on silica (Merck 9385) unless otherwise stated.

PREPARATION 1 N-Methyl-1H-indole-5-carboxamide

A mixture of methyl 1H-indole-5-carboxylate (2.5 g) and methylamine inwater (33%, 50 ml) was stirred at room temperature for 6 h. The solutionwas extracted with ethyl acetate (3×50 ml) and the organic extracts werecombined and dried. The solvent was removed in vacuo to give an oilwhich was chromatographed on silica (Kieselgel 60, 100 g) eluting withethyl acetate to give an oil (1.8 g), which solidifed to give the titlecompound on standing m.p. 140°-141°.

EXAMPLE 13-[1,2,3,6-Tetrahydro-1-(phenylmethyl)pyridin-4-yl]-1H-indole-5-carboxamidemaleate

A suspension of 1H-indole-5-carboxamide (0.4 g) in galcial acetic acid(20 ml) was heated to 80°under nitrogen, and the resulting solution wastreated with aqueous phosphoric acid (2N; 7 ml). Freshly distilled1-benzyl-4-piperidone (1.4 g) in glacial acetic acid (5 ml) was addedand the reaction mixture was stirred at 70° for 18 h, cooled, and pouredinto a mixture of ice and 0.88 ammonia solution (50 ml) with ice bathcooling. Ethyl acetate (50 ml) was added and the layers were separated.The aqueous layer was extracted with ethyl acetate (4×60 ml), and thecombined organic extracts were dried (MgSO₄) and evaporated to dryness.The resulting oil was chromatographed on Merck Kieselgel 60 (100 g)eluting with 10% methanol in ethyl acetate. Evaporation of the solventgave a foam which was treated with maleic acid in methanol/ether to givethe title compound as microcrystals (0.19 g), m.p. 164°-166°.

T.l.c. (SiO₂) ethylacetate:methanol (9:1) Rf 0.18

The following compounds were similarly prepared by condensation of theappropriate 5-substituted indole with an appropriate piperidone.

a) 3-(1,2,3,6-Tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamideas a solid (0.24 g), m.p. 228°-231° after chromatography eluting withmethanol.

T.l.c. (SiO₂) Ethyl acetate/isopropanol/water/ammonia (50:30:16:4) Rf0.6.

b)3-(1,2,3,6-Tetrahydro-1-methyl-4-pyridinyl)-1-methyl-1H-indole-5-carboxamideoxalate as a powder (0.1 g), m.p. 145°-150° after chromatography elutingwith dichloromethane/ethanol/0.88 ammonia (100:8:1)

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (50:8:1) Rf 0.25

EXAMPLE 2N-Methyl-3-(1,2,3,6-terahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamide(i) Methyl3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxylate

Following the method of Example 1, N-methyl-4-piperidone (-0.68 g) andmethyl 1H-indole-5-carboxylate (0.5 g) gave the title compound asmicrocrystals (0.18 g), m.p. 202°-204° following recrystallisation fromethyl acetate.

(ii)N-Methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamide

A solution of the product of stage (i) (0.5 g) in a mixture ofmethylamine in ethanol (40%, 20 ml) and methanol (10 ml) was heated atreflux for 10 h. The mixture was cooled, and partitioned between water(100 ml) and ethyl acetate (100 ml). The aqueous phase was separated,and extracted with ethyl acetate (50 ml). The organic layers werecombined, dried and evaporated in vacuo to give a solid, (0.25 g) whichwas crystallized twice from ethyl acetate to give the title compound asmicrocrystals (0.1 g), m.p. 125°-135°.

T.l.c. (SiO₂) Ethyl acetate/isopropanol/0.88 ammonia/water (25:15:8:2)Rf 0.4.

EXAMPLE 3 3-(1,2,3,6-Tetrahydro-4-pyridinyl)-1H-indole-5-carboxamide

A mixture of 1H-indole-5-carboxamide (1.8 g), 4-piperidone hydrochloridemonohydrate (3.4 g), and potassium hydroxide (11 g) in methanol (100 ml)was heated at reflux for 16 h. The mixture was cooled, and partitionedbetween ethyl acetate (200 ml) and saturated potassium carbonate (200ml). The aqueous phase was separated, and extracted with ethyl acetate(100 ml. The organic extracts were combined, dried and the solventevaporated in vacuo to give a semi-solid which was triturated withabsolute ethanol (10 ml), and washed with ether (3×20 ml). The resultantsolid was dried in vacuo to give the title compound, (1.1 g) m.p.225°-230°.

T.l.c. (SiO₂ (0.88 ammonia/methanol (1:24) Rf 0.17

The following compounds were similarly prepared from the appropriate5-substituted indole by condensation with an appropriate piperidone:

(a) N-Methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-5-carboxamide(0.4 g), m.p. 233°-236°.

T.l.c. (SiO₂) 0.88 ammonia/methanol (1:24) Rf 0.15

(b) 3-(1,2,3,6-Tetrahydro-1-methyl-4-pyridinyl)-1-H-indole-5-acetamidemaleate (0.083 g) m.p. 126°-127°.

T.l.c. (SiO₂) Ethyl acetate/isopropanol/water/0.88 ammonia (25:15:8:2)Rf 0.61

(c) 3-(1,2,3,6-Tetrahydro-4-pyridinyl)-1H-indole-5-acetamide maleate(0.18 g), m.p. 180°-181°

T.l.c. (SiO₂) Ethyl acetate/isopropanol/water/0.88 ammonia (25:15:8:2)Rf 0.46

(d) 3-(1,2,3,6-Tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-sulphonamideas a solid (0.3 g) m.p. 190°-200°, after chromatography eluting withethyl acetate/methanol/ammonia (180:20:1)

Analysis Found: C,57.1; H,6.3; N, 12.4. C₁₄ H₁₇ N₃ O₂ S.O.5C₄ H₈ O₂requires C,57.3; H,6.3; N,12.5%

(e)N,N-Dimethyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-sulphonamidehemihydrate as a solid (0.2 g), m.p. 230°-232°, after flashchromatography eluting with ethyl acetate

T.l.c. (SiO₂) Methylene chloride/ethanol/0.88 ammonia (50:10:1) Rf 0.35

(f)N-Methyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-methanesulphonamidehydrochloride as a solid (0.77 g), m.p. 120° (decomp), afterchromatography eluting with dichloromethane/ethanol/0.88 ammonia(100:8:1)

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (50:8:1) Rf 0.4

EXAMPLE 4N-Phenylmethyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamidehydrochloride hemihydrate (i) N-Phenylmethyl-1H-indole-5-carboxamide

Indole-5-carboxylic acid (3.0 g) in anhydrous terahydrofuran (THF) (25ml) was treated with 1,1-carbonyldiimidazole (CDI) (3.35 g) withstirring at room temperature for 1 h. A further amount (1.0 g) of CDIwas added and, after stirring for a further 1H, benzylamine (4.0 g) wasintroduced. Stirring was continued for 24 h. The solution was dilutedwith water (50 ml), saturated with sodium chloride, and the THF layerseparated off. The organic solution was washed with 1N hydrochlorideacid (3×50 ml), brine (2×50 ml), dried (MgSO₄) and evaporated underreduced pressure to given an oil (6.0 g) which was chromatographed onsilica (Merck 7734, 200 g) eluting with methylene chloride and thenmethylene chloride/methanol (50:1) to give a foam (4.0 g).Crystallization from ethyl acetate/petroleum/ether (b.p. 60°-80°) gavethe title compound as a solid (2.05 g) m.p. 155°-160°.

(ii)N-phenylmethyl-3-(1,2,3,6-Tetrahydro-1-methyl-4-pyridinyl-1H-indole-5-carboxamidehydrochloride hemihydrate

A solution of the product of stage (i) (1.0 g) in 2N methanolicpotassium hydroxide (64 ml) was treated with distilledN-methyl-4-piperidone (0.47 ml) and heated under reflux for 24 h withstirring. The mixture was concentrated in vacuo to approximately 10 mland diluted with water (40 ml(). The crude product separated as a solid(1.1 g) and was chromatographed on silica (Merck 7734, 100 g) elutingwith methylene chloride/ethanol/0.880 ammonium hydroxide(500:8:1)-(25:8:1) to give a solid (0.3 g). This material was suspendedin methanol 925 ml) and treated with excess ethereal hydrogen chloride.The solution was filtered, evaporated to dryness and the residuetriturated with anhydrous ether to give the title compound as a powder,(0.38 g) m.p. 279°-282°.

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (25:8) Rf 0.5

The following compounds were similarly prepared by reactingindole-5-carboxylic acid with an appropriate amine followed bycondensation with an appropriate piperidone:

(a)N-Phenylethyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamidehydrochloride as a foam (0.2 g), T.l.c. S₁ O₂, methylenechloride/ethanol/0.88 ammonia *(50:8:1), Rf 0.45

Analysis Found: C,66.9; H,6.45; N,9.7; C₂₃ H₂₅ N₃ O.HcL.0.82H₂ Orequires C,67.3; H,6.8; N,10.2%

(b)N-(1-Methylethyl)-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamidemaleate (0.43 g) as a powder, m.p. 175°-180°.

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (50:8:1) Rf 0.4

(c)N,N-Dimethyl-3-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)-1H-indole-5-carboxamideoxalate as a powder (0.06 g), m.p. 141°-146°, after chromatographyeluting with methylene chloride/ethanol/ammonia (100:8:1)

T.l.c. (SiO₂) ethanol/methylene chloride/0.88 ammonia (100:8:1) Rf 0.3

EXAMPLE 5N-(1-Methylethyl)-3-(1-Methyl-4-piperidinyl)-1H-indole-5-carboxamidehydrochloride

A suspension of 10% palladium oxide on carbon (0.85 g of a 50% paste inwater) in ethanol (50 ml) was stirred under hydrogen for 0.5 h. Asolution of the free base of the product of Example 4b (0.85 g) in amixture of 1:1 ethanol-methanol (200 ml) was added to the pre-reducedcatalyst and the mixture stirred under an atmosphere of hydrogen for 4h. The catalyst was filtered off and the solvent was removed by rotaryevaporation to give a foam (0.8 g) which was chromatographed on a columnof silica gel (40 g of Merck 7734) eluting with methylenechloride/ethanol/0.88 ammonia (50/8/1) to give the free base of thetitle compound as a foam (0.7 g). The free base (0.7 g) was dissolved inethanol (10 ml) and treated with excess ethereal hydrogen chloride.Removal of the solvent, by rotary evaporation, and drying under vacuumat 60° for 18 h gave the title compound as a foam (0.63 g) m.p.190°-200°.

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (50:8:1) Rf 0.2

The following compounds were similarly prepared:

(a) N-(2-Phenylethyl)-3-(1-methyl-4-piperidinyl)-1H-indole-5-carboxamidehydrochloride as a foam (0.39 g), m.p. 110°-115°, from the product ofExample 4a after chromatography eluting with methylenechloride/ethanol/ammonia.

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (25:8:1) Rf 0.75

(b) 3-(1-Methyl-4-piperidinyl)-1H-indole-5-carboxamide as a powder (1.09g), m.p. 118°-120°, from the product of Example 1a in ethanol (30ml)/water (40 ml).

T.l.c. (SiO₂) Ethyl acetate/isopropanol/water/ammonia (25:15:8:2) Rf 0.5

(c) N-Methyl-3-(4-piperidinyl)-1H-indole-5-carboxamide (0.2 g) m.p.227°-235°, from the product of Example 3a in ethanol and methanol (1:1).

T.l.c. (SiO₂) 0.88 ammonia/methanol (1:24) Rf 0.09

(d) 3-(4-Piperidinyl)-1H-indole-5-acetamide, maleate (0.16 g), m.p.140°-141°, from the product of Example 3c (0.3 g) in methanol.

T.l.c. (SiO₂) Ethyl acetate/isopropanol/water/ammonia (25:15:8:2) Rf0.39

(e) 3-(1-Methyl-4-piperidinyl)-1H-indole-5-acetamide (0.16 g) m.p.174°-175° from the product of Example 3b (0.3 g) in methanol.

T.l.c. (SiO₂) Ethyl acetate/isopropanol/water/ammonium (25:15:8:2) Rf0.49

(f) 1-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-carboxamide oxalateas a powder (0.53 g), m.p. 200°-205°, from the product of Example 1b inethanol (100 ml)/dimethylformamide (1 ml) after chromatography elutingwith methylene chloride/ethanol/0.88 ammonia (100:8:1)

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (25:8:1) Rf 0.5

(g) N,N-Dimethyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-carboxamideoxalate as a powder (0.24 g), m.p. 120°-125°, from the free base of theproduct of Example 4c after chromatography eluting with methylenechloride/ethanol/0.88 ammonia (100:8:1).

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (75:8:1) Rf 0.75

(h) 3-(1-Methyl-4-piperidinyl)-1H-indole-5-sulphonamide hydrochloride asa solid (0.1 g), m.p. 195°-198°, from the product of Example 3d inmethanol.

Analysis Found: C, 51.3; H,7.0; N,10.7. C₁₄ H₁₉ N₂ O₂ S.HCl.0.5H₂ O.C₃H₈ O requires C,51.2; H,7.3; N,10.5%.

(i) 3-(1-Methyl-4-piperidinyl)-1H-indole-5-methanesulphonamidehydrochloride as a powder (0.07 g), m.p. 140°-145° (dec.), from the freebase of the product of Example 3f after chromatography eluting withmethylene chloride/ethanol/0.88 ammonia (100:8:1).

T.l.c. (SiO₂) methylene chloride/ethanol/0.88 ammonia (50:8:1) Rf 0.25.

EXAMPLE 61-N-Dimethyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide(i) 5-Bromo-3-(1-methyl-4-piperidinyl)-1H-indole

A mixture of 5-bromoindole (39.2 g), N-methyl-4-piperidone (25.0 g) andpotassium hyroxide pellets (12.0 g) in methanol 9250 ml) was stirred andheated at reflux for 17 h then cooled to 5°, with stirring. The mixturewas filtered. The residue was washed consecutively with methanol, water,methanol again and ether and dried in vacuo to give the intermediatetetrahydropyridine (43.3 g) as a powder, with m.p. 256°-261° which wasused without further characterisation in the next stage. A solution ofethanolic hydrogen chloride was prepared by adding acetyl chloride (20ml) to ice-cooled, stirred ethanol (1.31). The intermediatetetrahydropyridine (43.2 g) was dissolved in a portion (0.95 l) of thissolution. The hydrochloride salt of the intermediate precipitated out.In order to redissolve this salt the suspension was heated on a steambath and portions of 2N hydrochloride acid (10 ml), water (15 ml) andcon. (11N) hydrochloric acid (10 ml) were added. The resultant solutionwas added to a prehydrogenated suspension of 5% platinum oxide on carbon(7.0 g) in ethanolic (HCl (0.351 of the above solution) and the mixturewas hydrogenated at room temperature and atmospheric pressure untiluptake of hydrogen ceased. The mixture was filtered and the solvent wasevaporated. The residue was suspended in ethyl acetate (600 ml). Sodiumcarbonate (2N; 350 ml) was added, with stirring and the mixture wasfiltered. The residue was washed with water and ethyl acetate and driedin vacuo to give the title compound (33.4 g) as a powder, m.p.160°-165°.

(ii) 5-Bromo-1-methyl-3-(1-methyl-4-piperidinyl)-1H-indole

The product of stage (i) (2.0 g) was dissolved in drieddimethylformamide (60 ml), and sodium hydride (330 mg dispersion in oil)was added at 5° under nitrogen. After stirring at 5° for 1 h, methyliodide (0.51 ml) was added at 5°, and the reaction mixture was stirredand warmed to room temperature over 1.5 h. The reaction mixture wastreated with 2N Na₂ CO₃ (100 ml), extracted with ethyl acetate (6×50 ml)and the combined organic phases were washed with brine (50 ml), dried(Na₂ SO₄), and evaporated in vacuo to give the title compound as an oil(720 mg) T.l.c. SiO₂, CH₂ Cl₂ :EtOH:NH₃ (100:8:1) Rf 0.1

(iii)(E)-N-Methyl-2-[1-Methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-yl]-ethenesulphonamide

A mixture of the product of stage (ii) (1.23 g), N-Methylethenesulphonamide (665 mg), tritethylamine (1.00 g), tri-o-tolylphosphine(447 mg) and palladium acetate (123 mg) in acetonitrile (9 ml) wasstirred and heated at 110° for 16 h in a sealed vessel. The reactionmixture was cooled to room temperature, and the solvent was evaporatedto leave a residue. The residue was combined with other impure batches(3.6 g in total) and was purified by `flash chromatography` (Merck Art,9385) eluting with CH₂ Cl₂ :EtOH:NH₃ 100:8:1) to give two impure productwas also rechromatographed using the same solvent system to give a foam(120 mg). This was combined with the initial batches of impure productand was rechromatographed by `flash chromatography` (Merck Art, 9385)eluting with CH₂ Cl:EtOH:NH₃ (200:8:1) to give the product as a foam.Trituration with diethyl ether at 5° gave the title compound as a solid(270 mg) m.p. 155°- 159°.

(iv) 1-N-Dimethyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulphonamide

A solution of the product of stage (iii) (240 mg) in ethanolic hydrogenchloride (40 ml) was hydrogenated at room temperature and atmosphericpressure over 10% palladium on carbon (50% w/w with H₂ O, 480 mg) untiluptake of hydrogen ceased. The catalyst was filtered and the filtratewas evaporated to leave a residue, which was dissolved in methanol (5ml) and the solution was basified with 2NNa₂ CO₃ (3 ml). The methanolwas evaporated and the residue was partitioned between water (10 ml) andethyl acetate (100 ml). The aqueous phase was further extracted withethyl acetate (2×100 ml) and the organic extracts were combined, washedwith brine (80 ml) dried (Na₂ SO₄), filtered and evaporated to give anoil. The oil was triturated with diethyl ether (80 ml) at 5° to give thetitle compound as a solid (144 mg) m.p. 95°-100°.

T.l.c. (SiO₂) dichloromethane/ethanol/0.88 ammonia (100:8:1) Rf 0.27

EXAMPLE 7 3-(1-Methyl-4-piperidinyl)-1H-indole-5-propanamide (i)5-Bromo-3-(1-methyl-4-piperidinyl)-1H-indole

A mixture of 5-bromoindole (39.2 g), N-methyl-4-piperidone (25.0 g) andpotassium hydroxide pellets (12.0 g) in methanol (9250 ml) was stirredand heated at reflux for 17 h then cooled to 5°, with stirring. Themixture was filtered. The residue was washed consecutively withmethanol, water, methanol again and ether and dried in vacuo to give theintermediate tetrahydropyridine (43.3 g) as a powder, with m.p.256°-261° which was used without further characterisation in the nextstage. A solution of ethanolic hydrogen chloride was prepared by addingacetyl chloride (20 ml) to ice cooled, stirred ethanol (1.3l). Theintermediate tegrahydropyridine (43.2 g) was dissolved in a portion(0.95 l) of this solution. The hydrochloride salt of the intermediateprecipitated out. In order to redissolve this salt the suspension washeated on a steam bath and portions of 2N hydrochloric acid (10 ml),water (15 ml) and conc. (11N) hydrochloric acid (10 ml) were added. Theresultant solution was added to a prehydrogenated suspension of 5%platinum oxide on carbon (7.0 g) in ethanolic (HCl (0.351 of the abovesolution) and the mixture was hydrogenated at room temperature andatmospheric pressure until uptake of hydrogen ceased. The mixture wasfiltered and the solvent was evaporated. The residue was suspended inethyl acetate (600 ml). Sodium carbonate (2N; 350 ml) was added, withstirring and the mixture was filtered. The residue was washed with waterand ethyl acetate and dried in vacuo to give the title compound (33.4 g)as a powder, m.p. 160°-165°.

(ii) (E)-3-[3-(1-Methyl-4-piperidinyl)-1H-indol-5-yl]propenamide

A mixture of the product of stage (i) (1.00 g, acrylamide (317 mg)palladium acetate (50 mg), tri-o-tolylphosphine (300 mg) andtriethylamine (0.50 ml) in acetonitrile (7 ml) was stirred and heated ina sealed vessel (10 ml) at 100° for 18 h. The supernatant was decantedand evaporated in vacuo to a solid. The tarry residue remaining in thesealed vessel was extracted with hot methanol (10 ml) and the solutioncombined with the solid obtained above. The mixture was applied to thetop of a silica gel column and eluted with a mixture ofdichloromethane:ethanol:0.88 ammoni (50:8:1). Evaporation of the solventin vacuo from the appropriate fractions gave the title compound as anoil (660 mg) which solidified on standing mp 82°-83.5°.

(iii) 3-(1-Methyl-4-piperidinyl)-1H-indole-5-propanamide

A solution of the product of stage (ii) (650 mg) in ethanolic hydrogenchloride was hydrogenated over pre-reduced 10% palladium on carbon (0.20g of a 50% w/w paste with water) at 25° and atmospheric pressure for 24h. The catalyst was removed by filtration and the solvent evaporated invacuo to give a foam. The residue was purified by flash columnchromatography eluting with dichloromethane:ethanol:0.88 ammonia(50:8:1). Evaporation of the solvent in vacuo from the appropriatefractions gave the title compound as a foam (188 mg).

T.l.c. SiO₂ [CH₂ Cl₂ :EtOH:0.88 NH₃ 50:8:1] Rf 0.20.

I.r. (CHBr₃) NH₂ (3520 and 3400) NMe (2785 and 2735) C═O (1678)NH(1588)cm⁻¹.

EXAMPLE 8 N-methyl-3(1-methyl-4-piperidinyl)-1H-indole-5-propanamideoxalate (i)(E)-N-methyl-3-[3-(1-methyl-4-piperidinyl)-1H-indole-5-yl]propaneamide

A mixture of 5-bromo-3-(1-methyl-4-piperidinyl)-1H-indole (1.0 g),N-methyl-propenamide (0.38 g), palladium acetate (50 mg),tri-o-tolylphosphine (0.3 g) in a mixture of triethylamine (0.5 ml) andacetonitrile (7 ml) were heated at 100° in a sealed vessel for 24 h. Theresulting mixture was evaporated in vacuo and the residue purified byflash chromatography eluting with dichloromethane, ethanol, ammonia(50:8:1) to give the title compound as a solid (1.0 g).

T.l.c. SiO₂, CH₂ Cl₂ /EtOH/NH₃ (50:8:1) Rf 0.3.

(ii) N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-propanamide oxalate

A solution of the product of stage (i) (1.0 g) in ethanolic hydrogenchloride (100 ml(was hydrogenated over pre-reduced 10% palladium oncarbon (50% w/w paste with water, 0.2 g) at room temperature andatmospheric pressure for 17 h. The catalyst was removed by filtrationand the cake washed with hot ethanol (50 ml). The combined filtrateswere evaporated in vacuo and purified by flash chromatography elutingwith a mixture of CH₂ Cl₂ /EtOH/NH₃ (50:8:1) to give the free base as anoil (0.5 g).

To a stirred solution of the free base (0.5 g) in methylisobutyl ketone(MIBK) (7 ml) at room temperature was added dropwise, a solution ofoxalic acid (53.9 mg) in MIBK (3 ml). The resulting suspension wasstirred for 5 min, and the solid collected by filtration and washed withMIBK (5 ml). The solid was dried in vacuo at 25° for 6 h end 40° for 2 hto give the title compound as a solid (0.243 g) m.p. 65°-70° (decomp).

T.l.c. SiO₂, CH₂ Cl₂ /EtOH/NH₃ (50:8:1) Rf 0.3.

The following example illustrates a pharmaceutical formulation accordingto the invention containing a compound of the invention as the activeingredient.

Tablets for Oral Administration

    ______________________________________                                                        mg/tablet                                                     ______________________________________                                        Active Ingredient 10                                                          Magnesium Stearate BP                                                                           0.5                                                         Anhydrous Lactose 99                                                          ______________________________________                                    

The active ingredient is sieved and blended with the anhydrous lactoseand magnesium stearate. The mix is then compressed into tablets using aManasty F₃ tablet machine fitted with 8.0 mm concave punches.

Injection for Intravenous Administration

    ______________________________________                                                        mg/ml                                                         ______________________________________                                        Active Ingredient 0.6 mg                                                      Sodium Chloride BP                                                                              as required                                                 Water for Injection BP                                                                          1.0 ml                                                      ______________________________________                                    

Sodium chloride may be added to adjust the tonicity of the solution andthe pH may be adjusted, using acid or alkali, to that of optimumstability and/or to facilitate solution of the active ingredient.Alternatively suitable buffer salts may be used.

The solution was prepared, clarified and filled into appropriate sizeampoules sealed by fusion of the glass. The injection is sterilised byheating in an autoclave using one of the acceptable cycles.

Alternatively the solution may be sterilised by filtration and filledinto sterile ampoules under aseptic conditions. The solution may bepacked under an inert atmosphere of nitrogen or other suitable gas.

We claim:
 1. A compound of formula (I) ##STR13## wherein R₁ represents ahydrogen atom, or a C₁₋₆ alkyl group;R₂ represents a hydrogen atom, aC₁₋₆ alkyl group, a C₃₋₇ cycloalkyl group, a C₃₋₆ alkenyl group, or aphenyl or phen(C₁₋₃) alkyl group in which the phenyl ring is optionallysubstituted by a halogen atom, a C₁₋₄ alkoxy group, a hydroxy group or aC₁₋₃ alkyl group; R₃ represents a hydrogen atom, a C₁₋₃ alkyl group or agroup --CO₂ R₅, --COR₅, --COCO₂ R₅ or --CONHR₅, where R₅ represents ahydrogen atom, a C₁₋₄ alkyl group, a C₃₋₇ cycloalkyl group, a C₂₋₄alkenyl group or an aryl or ar(C₁₋₄)alkyl group in which the aryl groupis phenyl which may be unsubstituted or substituted by a halogen atom, aC₁₋₄ alkoxy group, a C₁₋₄ alkyl group or a hydroxy group, provided thatwhen R₃ represents --CO₂ R₅, R₅ is other than hydrogen; R₄ represents ahdyrogen atom, a C₁₋₃ alkyl group, a C₃₋₆ alkenyl group, a phenyl groupor a phen(C₁₋₃)alkyl group; A--B represents the group CH--CH₂ -- orC═CH--; D represents the group --SO₂ --; n represents zero or an integerfrom 1 to 5;or a pharmaceutically acceptable salt or solvate thereof,provided that when n is 2, R₃ is hydrogen and R₄ is hydrogen or C₁₋₃alkyl, then R₂ is other than hydrogen or C₁₋₆ alkyl.
 2. A compoundaccording to claim 1, wherein, in the formula (I), A--B represents thegroup --CH--CH₂ --.
 3. A compound according to claim 1, wherein, in theformula (I), R₁ represents a hydrogen atom or a C₁₋₃ alkyl group.
 4. Acompound according to claim 1, wherein, in the formula (I), R₂represents a hydrogen atom or a C₁₋₃ alkyl group.
 5. A compoundaccording to claim 1, wherein, in the formula (I), R₁ and R₂ togethercomprise from 1 to 3 carbon atoms, and when R.sub. and R₂ comprise 1carbon atom, then one of R₁ or R₂ is hdyrogen.
 6. A compound accordingto claim 1, wherein, in the formula (I), R₃ represents a hydrogen atom.7. A compound according to claim 1, wherein, in the formula (I), R₄represents a C₁₋₃ alkyl group.
 8. A compound according to claim 1,wherein, in the formula (I), n represents 0, 1 or
 2. 9. A compoundaccording to claim 1, wherein in formula (I), n represents 1,2,3,4 or 5.10. A compound of formula (I) ##STR14## wherein R₁ represents a hydrogenatom or a C₁₋₆ alkyl group;R₂ represents a hydrogen atom, a C₁₋₆ alkylgroup, a C₃₋₇ cycloalkyl group, a C₃₋₆ alkenyl group, or a phenyl orphen(C₁₋₃) alkyl group in which the phenyl ring is optionallysubstituted by a halogen atom, a C₁₋₄ alkoxy group, a hydroxy group or aC₁₋₃ alkyl group; R₃ represents a hydrogen atom, a C₁₋₃ alkyl group or agroup --CO₂ R₅, --COR₅, --COCO₂ R₅ or --CONHR₅, where R₅ represents ahydrogen atom, a C₁₋₄ alkyl group, a C₃₋₇ cycloalkyl group, a C₂₋₄alkenyl group or an aryl or ar(C₁₋₄)alkyl group in which the aryl groupis phenyl which is phenyl which may be unsubstituted or substituted by ahalogen atom, a C₁₋₄ alkoxy group, a C₁₋₄ alkyl group or a hydroxygroup, provided that when R₃ represents --CO₂ R₅, R₅ is other thanhydrogen; R₄ represents a hydrogen atom, a C₁₋₃ alkyl group, a C₃₋₆alkenyl group, a phenyl group or a phen(C₁₋₃)alkyl group; A--Brepresents the group CH--CH₂ -- or C═CH--; D represents the group --SO₂-- or --CO--; n represents the integer from 1 to 5;or a pharmaceuticallyacceptable salt or solvate thereof, provided that when n is 2, R₃ ishydrogen and R₄ is hydrogen or C₁₋₃ alkyl, then R₂ is other thanhydrogen or C₁₋₆ alkyl.
 11. A compound according to claim 10, wherein informula (I), D represents the group --SO₂ --.
 12. A compound accordingto claim 10, wherein in formula (I), D represents the group --CO--. 13.A compound according to claim 10, wherein in formula (I), A--Brepresents the group --CH--CH₂ --.
 14. A compound according to claim 10,wherein in formula (I), R₁ represents a hydrogen atom or a C₁₋₃ alkylgroup.
 15. A compound according to claim 10, wherein in formula (I), R₂represents a hydrogen atom or a C₁₋₃ alkyl group.
 16. A compoundaccording to claim 10, wherein, in the formula (I), R₁ and R₂ togethercomprise from 1 to 3 carbon atoms, and when R₁ and R₂ comprise 1 carbonatom, then one of R₁ or R₂ is hydrogen.
 17. A compound according toclaim 9, wherein in formula (I), R₃ represents a hydrogen atom.
 18. Acompound according to claim 9, wherein in formula (I), R₄ represents aC₁₋₃ alkyl group.
 19. A compound according to claim 9, wherein informula (I), n represents 1 or
 2. 20. A compound of formula (Ia)##STR15## wherein R_(1a) represents a hydrogen atom or a C₁₋₆ alkylgroup;R_(2a) represents a hydrogen atom or a C₁₋₆ alkyl group; R_(3a)represents a hydrogen atom or a C₁₋₃ alkyl group; R_(4a) represents ahydrogen atom or a C₁₋₃ alkyl group;or a pharmaceutically acceptablesalt or solvate thereof.
 21. A pharmaceutical composition for use in thetreatment of conditions associated with cephalic pain which comprises aneffective amount to treat conditions associated with cephalic pain of atleast one compound of formula (I) as defined in claim 1 or apharmaceutically acceptable salt or solvate thereof together with one ormore pharmaceutically acceptable carriers or excipients.
 22. Apharmaceutical composition as claimed in claim 21 wherein the conditionsassociated with cephalic pain are migraine, cluster headache, chronicparoxysmal hemicrania or headache associated with vascular disorders.23. A pharmaceutical composition as claimed in claim 21 adapted fororal, parenteral or intranasal administration.
 24. A method of treatinga human susceptible to or suffering from migraine, cluster headache,chronic paroxysmal hemicrania or headache associated with vasculardisorder which comprises administering an effective amount of a compoundof formula (I) ##STR16## wherein R₁ represents a hydrogen atom or a C₁₋₆alkyl group;R₂ represents a hydrogen atom, a C₁₋₆ alkyl group, a C₃₋₇cycloalkyl group, a C₃₋₆ alkenyl group, or a phenyl or phen(C₁₋₃)alkylgroup in which the phenyl ring is optionally substituted by a halogenatom, a C₁₋₄ alkoxy group, a hydroxy group or a C₁₋₃ alkyl group; R₃represents a hydrogen atom, a c₁₋₃ alkyl group or a group --CO₂ R₅,--COR₅, --COCO₂ R₅ or --CONHR₅ wherein R₅ represents a hydrogen atom, aC₁₋₄ alkyl group, a C₃₋₇ cycloalkyl group, a C₂₋₄ alkenyl group or anaryl or ar(C₁₋₄)alkyl group in which the aryl group may be unsubstitutedor substituted by a halogen atom, a C₁₋₄ alkoxy group, a C₁₋₄ alkylgroup or a hydroxy group (provided that when R₃ represents --CO₂ R₅, R₅is other than hydrogen) R₄ represents a hydrogen atom, a C₁₋₃ alkylgroup, a c₃₋₆ alkenyl group, a phenyl group or a phen(C₁₋₃)alkyl group;A--B represents the group CH--CH₂ -- or C═CH--; D represents the group--CO-- or --SO₂ --; n represents zero or an integer from 1 to 5;provided that when D represents the group --SO₂ --, n is 2, R₃ ishydrogen and R₄ is hydrogen or C₁₋₃ alkyl, then R₂ is other thanhydrogen or C₁₋₆ alkyl;or a pharmaceutically acceptable salt or solvatethereof to said human.
 25. A method of treating a human susceptible toor suffering from migraine, cluster headache, chronic paroxysmalhemicrania or headache associated with vascular disorders whichcomprises administering a pharmaceutical composition according to claim21.